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1.  Negative correlation between bone mineral density and TSH receptor antibodies in long-term euthyroid postmenopausal women with treated Graves’ disease 
Thyroid Research  2013;6:11.
Thyrotoxicosis is a cause of secondary osteoporosis. High concentrations of triiodotironine (T3) in Graves’ disease stimulate bone turnover, but it is unclear if euthyroidism will always normalize bone metabolism. Thyrotropin (TSH) is known to affect directly the bone metabolism through the TSH receptor and TSH receptor antibodies (TRAb) may have an important role in bone turn-over.
The aim of our study was to determine, in pre and postmenopausal euthyroidism patients with previous overt hyperthyroidism due to Graves’ disease the bone mineral density (BMD) as well as factors that could affect BMD in each group, including TRAb.
Cross-sectional, non-interventional study. Fifty-seven patients with previous hyperthyroidism due to Graves’ disease (premenopausal: 30, postmenopausal: 27) that remained euthyroid for at least 6 months prior to study were included and compared with fifty- two matched respective controls. Thyrotoxine (T4), TSH, TRAb and BMD were measured.
Only euthyroid postmenopausal patients with a history of hyperthyroidism due to Graves’ disease showed lower whole body BMD than matched controls. The BMD expressed as Z-score was less in whole body and lumbar spine in postmenopausal in relation to premenopausal women with previous overt hyperthyroidism due to Graves’ disease.
In the postmenopausal patients, the Z-score of lumbar spine BMD correlated negatively with TRAb (r = −0,53, p < 0.008), positively with the time of evolution of the disease (r = +0.42, p < 0.032) and positively with the time of euthyroidism (r = + 0.50, p < 0.008), but neither with serum T4 nor TSH. In a multiple regression analysis TRAb was the only significant independent variable in relation to lumbar spine BMD (F = 3. 90, p < 0.01).
In euthyroid women with a history of Graves’ hyperthyroidism, BMD was only affected in the postmenopausal group. The negative correlation of Z-score of lumbar spine BMD with TRAb suggests that this antibody may affect the bone metabolism.
PMCID: PMC3847206  PMID: 24020400
2.  Bone mineral density in patients of Graves disease pre- & post-treatment in a predominantly vitamin D deficient population 
Background & objectives:
Hyperthyroidism causes bone loss, and its treatment may restore bone mass, however, concomitant vitamin D deficiency may prevent this. We undertook this study to measure the bone mineral density (BMD) 25 (OH) vitamin D levels in patients with Graves disease in our population which is predominently vitamin D deficient and how we change with when patients become euthyroid.
The biochemical, thyroid functions, serum vitamin D levels and BMD were estimated in 80 consecutive patients with Graves and 80 euthyroid controls. Patients were treated and rendered euthyroid. Fifty four completed one year, and 27 completed two years of follow up.
Patients had significant reduced BMD during hyperthyroid state compared to normal healthy controls. The mean vitamin D levels at baseline were in the insufficient range both patients (12.67±6.24 ng/ml) and controls (10.99±7.05 ng/ml). The BMD improved at all sites with antithyroid treatment. But, the BMD adjusted for body mass index (BMI) and age at all sites showed significant decrease with time.
Interpretation & conclusions:
Age and body mass index positively correlated with BMD. There was improvement in absolute BMD of patients at one and two years of follow up. When the BMD was adjusted for age and BMI, there was a decrease in BMD at one year which was less in the second year including that the damage in BMD caused by thyroid hormone excess is not made up even after two years of patient being euthyroid. Whether vitamin D replacement would change this needs to be studied.
PMCID: PMC3307182  PMID: 22382181
Bone mineral density; Graves’disease; hyperthyroidism; vitamin D deficiency
3.  Weight homeostasis & its modulators in hyperthyroidism before & after treatment with carbimazole 
Background & objectives:
Hyperthyroidism is associated with increased food intake, energy expenditure and altered body composition. This study was aimed to evaluate the role of adipocytokines in weight homeostasis in patients with hyperthyroidism.
Patients (n=27, 11men) with hyperthyroidism (20 Graves’ disease, 7 toxic multinodular goiter) with mean age of 31.3±4.2 yr and 28 healthy age and body mass index (BMI) matched controls were studied. They underwent assessment of lean body mass (LBM) and total body fat (TBF) by dual energy X-ray absorptiometer (DXA) and blood sample was taken in the fasting state for measurement of leptin, adiponectin, ghrelin, insulin, glucose and lipids. Patients were re-evaluated after 3 months of treatment as by that time all of them achieved euthyroid state with carbimazole therapy.
The LBM was higher (P<0.001) in healthy controls as compared to hyperthyroid patients even after adjustment for body weight (BW), whereas total body fat was comparable between the two groups. Serum leptin levels were higher in patients with hyperthyroidism than controls (22.3±3.7 and 4.1±0.34 ng/ml, P<0.001), whereas adiponectin levels were comparable. Plasma acylated ghrelin was higher in patients than in controls (209.8±13.3 vs 106.2±8.2 pg/ml, P<0.05). Achievement of euthyroidism was associated with significant weight gain (P<0.001) and significant increase in lean body mass (P<0.001). The total body fat also increased but insignificantly from 18.4±1.8 to 19.9±1.8 kg. There was significant decrease (P<0.05) in serum leptin and acylated ghrelin but adiponectin levels remained unaltered after treatment. Serum leptin positively correlated with TBF and this correlation persisted even after adjustment for BW, BMI, gender and age (r=0.62, P=0.001). However, serum leptin and acylated ghrelin did not correlate with the presence or absence of hyperphagia.
Interpretation & conclusion:
Patients with hyperthyroidism predominantly had decreased lean body mass which increased after achievement of euthyroidism with carbimazole. The hyperphagia and the alterations in weight homeostasis associated with hyperthyroidism were independent of circulating leptin and ghrelin levels.
PMCID: PMC3461736  PMID: 22960891
Adipocytokines; body composition; ghrelin; hyperphagia; hyperthyroidism
4.  Alendronate increases BMD at appendicular and axial skeletons in patients with established osteoporosis 
To identify high-risk patients and provide pharmacological treatment is one of the effective approaches in prevention of osteoporotic fractures. This study investigated the effect of 12-month Alendronate treatment on bone mineral density (BMD) and bone turnover biochemical markers in postmenopausal women with one or more non-traumatic fractures, i.e. patients with established osteoporosis.
A total of 118 Hong Kong postmenopausal Chinese women aged 50 to 75 with low-energy fracture at distal radius (Colles' fracture) were recruited for BMD measurement at lumbar spine and non-dominant hip using Dual-Energy X-ray Absorptiometry (DXA). 47 women with BMD T-score below -2 SD at either side were identified as patients with established osteoporosis and then randomized into Alendronate group (n = 22) and placebo control group (n = 25) for BMD measurement at spine and hip using DXA and distal radius of the non-fracture side by peripheral quantitative computed tomography (pQCT), and bone turnover markers, including bone forming alkaline phosphatase (BALP) and bone resorbing urinary Deoxypyridinoline (DPD). All measurements were repeated at 6 and 12 months.
Alendronate treatment significantly increased BMD, more in weight-bearing skeletons (5.1% at spine and 2.5% at hip) than in non-weight bearing skeleton (0.9% at distal radius) after 12 months treatment. Spine T-score was significant improved in Alendronate group (p < 0.01) (from -2.2 to -1.9) but not in control placebo group. The Alendronate treatment effect was explained by significant suppression of bone turnover.
12 months Alendronate treatment was effective to increase BMD at both axial and appendicular skeletons in postmenopausal women with established osteoporosis.
PMCID: PMC1885425  PMID: 17511887
5.  Metabolic and Clinical Consequences of Hyperthyroidism on Bone Density 
In 1891, Von Recklinghausen first established the association between the development of osteoporosis in the presence of overt hyperthyroidism. Subsequent reports have demonstrated that BMD loss is common in frank hyperthyroidism, and, to a lesser extent, in subclinical presentations. With the introduction of antithyroid medication in the 1940s to control biochemical hyperthyroidism, the accompanying bone disease became less clinically apparent as hyperthyroidism was more successfully treated medically. Consequently, the impact of the above normal thyroid hormones in the pathogenesis of osteoporosis may be presently underrecognized due to the widespread effective treatments. This review aims to present the current knowledge of the consequences of hyperthyroidism on bone metabolism. The vast number of recent papers touching on this topic highlights the recognized impact of this common medical condition on bone health. Our focus in this review was to search for answers to the following questions. What is the mechanisms of action of thyroid hormones on bone metabolism? What are the clinical consequences of hyperthyroidism on BMD and fracture risk? What differences are there between men and women with thyroid disease and how does menopause change the clinical outcomes? Lastly, we report how different treatments for hyperthyroidism benefit thyroid hormone-induced osteoporosis.
PMCID: PMC3736466  PMID: 23970897
6.  Low bone turnover and low bone density in a cohort of adults with Down syndrome 
Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem.
To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults.
Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption.
Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z≤−2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2±5.2 ng/ml vs. 2.2±0.9 ng/ml in the DS group (P= 0.002). Serum CTx levels in the normal group were 0.4± 0.1 ng/ml vs. 0.3±0.1 ng/ml (P=0.369).
Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.
PMCID: PMC3606288  PMID: 22903293
Bone density; Bone turnover; Down syndrome; Osteopenia; Osteoporosis; Trisomy 21
7.  Bone mineral density and bone turnover in spinal osteoarthrosis. 
Annals of the Rheumatic Diseases  1995;54(11):867-871.
OBJECTIVES--To determine whether there was a generalised increase in bone mineral density (BMD) in spinal osteoarthrosis (OA), and to determine the mechanism of this possible protection against osteoporosis as assessed by biochemical markers of bone turnover. METHODS--We studied 375 women (ages 50 to 85) from a population based group. Spinal OA was defined from radiographs as the presence of degenerative changes affecting intervertebral or facet joints. BMD of the lumbar spine (LS), femoral neck (FN) and total body (TB) was measured by dual energy x ray absorptiometry (Lunar DPX). Bone turnover rates were estimated from measurement of biochemical markers of bone formation and resorption (urine deoxypyridinoline (Dpyr) and serum bone specific alkaline phosphatase (BAP)). RESULTS--BMD at each site was greater in the women with spinal OA (mean increase in LS-BMD 7.9%, 95% confidence interval (CI) 1.0 to 15.1; TB-BMD 8.4%, 95% CI 1.9 to 9.7; FN-BMD 6.4%, 95% CI 0.3 to 12.6). Twenty four hour urinary excretion of Dpyr, corrected for TB bone mineral content, and serum BAP were 19% lower in the women with spinal OA (95% CI for Dpyr 4.3 to 31.9%; for BAP 6.3 to 32.0%). CONCLUSIONS--Spinal OA is associated with a generalised increase in BMD and a decreased rate of bone turnover. This suggests that the protective effect of spinal OA against osteoporosis may be mediated by decreased bone turnover.
PMCID: PMC1010035  PMID: 7492234
8.  Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density 
In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis.
This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to −2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs).
Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD.
Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.
PMCID: PMC3206165  PMID: 21365462
Bone turnover markers; IGF-1; Premenopausal osteoporosis
9.  Relative Contributions of Multiple Determinants to Bone Mineral Density in Men 
Osteoporosis in men has gained recognition as a public health problem, generating an interest in the search for risk factors. Isolation of individual risk factors could allocate disproportionate attention to relationships that may be of limited consequence.
The Boston Area Community Health/Bone (BACH/Bone) Survey is a population-based study of randomly-selected community-dwelling men (age 30-79 y). Bone mineral density (BMD) and lean mass were measured by dual x-ray absorptiometry. Socioeconomic status, health history, and lifestyle factors were obtained via interview. Hormone levels and markers of bone turnover were obtained from non-fasting blood samples. Multivariate analyses measured relative contributions of covariates to femoral neck (hip), 1/3 distal radius (wrist), and lumbar spine BMD.
Factors positively associated with BMD in multivariate models at the three sites were black race and appendicular lean mass. Asthma was consistently negatively associated. Various other risk factors also contributed significantly to each of the individual sites. R2 values for the hip, wrist, and spine were 41%, 30%, and 24% respectively. Lean mass accounted for the most explained variance at all three sites.
These data emphasize the limitation of focusing on individual risk factors and highlight the importance of potentially modifiable lean mass in predicting BMD.
PMCID: PMC2836411  PMID: 19319620
aging; body composition; bone mineral density; men; population studies
10.  Bone turnover in elderly men: relationships to change in bone mineral density 
It is not clear whether bone turnover markers can be used to make inference regarding changes in bone mineral density (BMD) in untreated healthy elderly men. The present study was designed to address three specific questions: (i) is there a relationship between bone turnover markers and femoral neck BMD within an individual; (ii) is there a relationship between baseline measurements of bone turnover markers and subsequent change in BMD; and (iii) is there a relationship between changes in bone turnover markers and changes in femoral neck BMD?
The present study was part of the on-going Dubbo Osteoporosis Epidemiology Study, which was designed as a prospective investigation. Men who had had at least 3 sequential visits with serum samples available during follow-up were selected from the study population. Serum C-terminal telopeptide of type I collagen (sICTP), N-terminal propeptide of type I collagen (sPINP) and femoral neck BMD were measured by competitive radioimmunoassays. Femoral neck bone mineral density (BMD) was measured by a densitometer (GE Lunar Corp, Madison, WI). Various mixed-effects models were used to assess the association between the markers and changes in BMD.
One hundred and one men aged 70 ± 4.1 years (mean ± SD) met the criteria of selection for analysis. On average, sPINP decreased by 0.7% per year (p = 0.026), sICTP increased by 1.7% per year (p = 0.0002), and femoral neck BMD decreased by 0.4% per year (p < 0.01). Within-subject analysis indicated that changes in BMD were significantly associated with changes in sPINP (p = 0.022), but not with changes in sICTP (p = 0.84). However, neither baseline sPINP (p = 0.50) nor baseline sICTP (p = 0.63) was associated with subsequent changes in BMD. Moreover, changes in BMD were not significantly associated with previous changes in sPINP (p = 0.13) or sICTP (p = 0.95).
These results suggest that in elderly men of Caucasian background, changes in sPINP were inversely related to changes in BMD within an individual. However, neither sPINP nor sICTP was sufficiently sensitive to predict the rate of change in BMD for a group of individuals or for an individual.
PMCID: PMC1808057  PMID: 17316428
11.  BMD and Serum Intact Osteocalcin in Postmenopausal Osteoporosis Women 
India seems to have the highest prevalence of osteoporosis. With growing awareness of osteoporosis and its impact on life span especially in India, special attention is being paid to early detection, management and treatment of postmenopausal osteoporosis in women. Measurement of BMD and osteocalcin are of value in estimating bone turnover rates. The aim of this study is (1) to measure the specific, sensitive bone formation marker such as osteocalcin and BMD in postmenopausal osteoporosis women and postmenopausal non-osteoporosis women; (2) the follow up study to evaluate the impact of specific antiresorptive therapy (alendronate + calcium + vitamin D) regimen in postmenopausal osteoporosis by assaying osteocalcin and BMD. Sixty clinically diagnosed postmenopausal osteoporosis patients and 60 normal subjects (postmenopausal non-osteoporosis women) were recruited as control. Mean bone mineral density T score and Z score was significantly decreased (P < 0.001) in postmenopausal osteoporosis patients as compared to controls. Highly significant increase in the mean score of BMD—T score and Z score from baseline to post therapy of 3 months was observed in postmenopausal osteoporosis women. Serum osteocalcin levels were significantly increased (P < 0.001) as compared to control group. Serum osteocalcin levels were decreased significantly (P < 0.001) from baseline to post therapy of 3 months in postmenopausal osteoporosis women. BMD is the best quantifiable predictor of osteoporotic fracture and osteocalcin is specific, sensitive, promising, currently used marker for better prognosis of osteoporosis and for monitoring responses to antiresorptive therapy.
PMCID: PMC3068775  PMID: 22211018
Bone formation marker; Bone mineral density; Postmenopausal osteoporosis
12.  Differential effects of endocrine dysfunction on the axial and the appendicular skeleton. 
Journal of Clinical Investigation  1982;69(6):1302-1309.
In 100 patients with various types of endocrine dysfunction, we measured bone mineral density (BMD) at the midradius (greater than 95% cortical bone) and distal radius (75% cortical and 25% trabecular bone) by single photon absorptiometry and at the lumbar spine (greater than 66% trabecular bone) using the new technique of dual photon absorptiometry. BMD in each endocrine disorder deviated in at least one site from the sex-specific age regression of 187 normal subjects. For patients with primary hyperparathyroidism, hypercortisolism, and hyperthyroidism this deviation was negative (suggesting bone loss), whereas for patients with secondary hyperparathyroidism due to chronic renal failure, acromegaly, and postsurgical hypoparathyroidism it was positive (suggesting bone gain). When all six states of endocrine dysfunction were compared concomitantly by multivariate analysis of variance, the profile of the changes in BMD differed significantly (P less than 0.001), indicating a nonuniform response of bone to the various hormonal alterations. When values for BMD at each of the three scanning sites were compared the midradius and distal radius did not differ significantly; either of the radius measurements, however, differed significantly (P less than 0.001) from the lumbar spine. Thus, the BMD of the axial skeleton cannot be reliably predicted from measurements made in the appendicular skeleton. We conclude that the effects of endocrine dysfunction on bone density are complex and are both disease and site specific.
PMCID: PMC370203  PMID: 7085876
13.  Evaluation of bone metabolism and bone mass in patients with type-2 diabetes mellitus. 
The objectives of this study were to determine whether type-2 diabetes was associated with a higher bone mineral density (BMD) in men and women and to evaluate the differences in mineral metabolism between diabetic and normal subjects by using biochemical bone turnover markers. In this study, 52 patients (37 females/15 males) aged 41-64 with type-2 diabetes mellitus and 48 nondiabetic control subjects (34 females/14 males) were evaluated. In men, BMD was significantly higher in diabetics at the forearm (p <0.05), whereas in women tended to be higher at the hip (p=0.002). Serum osteocalcin (p<0.0001), bone alkaline phosphatase (BAP) (p<0.05) and carboxyterminal telopeptide (CTx) (p<0.05) were higher in the control group than in diabetics. In men, serum osteocalcin (p<0.05) and CTx (p<0.005) and, in women, serum osteocalcin (p<0.0001) and BAP (p<0.05) were lower in diabetic subjects. In conclusion, our findings suggest that although bone formation is decreased in type-2 diabetes, diabetic patients are not susceptible to bone resorption. This low bone turnover can slow the rate of bone loss and cause a higher bone density than expected for their age.
PMCID: PMC2569751  PMID: 17052049
14.  Use of Alendronate Sodium (Fosamax) to Ameliorate Osteoporosis in Renal Transplant Patients: A Case-Control Study 
PLoS ONE  2012;7(11):e48481.
Renal transplant patients often have severe bone and mineral deficiencies. While the clinical effects of immunosuppressive agents like calcineurin inhibitors (CIs) and sirolimus on bone turnover are unclear, bisphosphonates are effective in bone recovery in these patients. Gender is significantly associated with osteoporosis and affects bone turnover, which is different in women and men. The effective gender-related site of action of bisphosphonates is unknown.
Initially, we enrolled 84 kidney recipients who had received their transplants at least 5 months ago; of these, 8 were excluded and 76 were finally included in the study. First bone mineral density (BMD) at the lumbar spine, hip, and femoral neck was determined using dual-energy X-ray absorptiometry (DXA) between September 2008 and March 2009. These 76 patients underwent a repeat procedure after a mean period 14 months. Immunosuppressive agents, bisphosphonates, patients' characteristics, and biochemical factors were analyzed on the basis of the BMD determined using DXA.
After the 14-month period, the BMD of lumbar spine increased significantly (from 0.9 g/cm2 to 0.92 g/cm2, p<0.001), whereas that of the hip and femoral neck did not. Ordinal logistic regression analysis was used to show that Fosamax improved bone condition, as defined by WHO (p = 0.007). The use of immunosuppressive agents did not affect bone turnover (p>0.05). Moreover, in subgroup analysis, Fosamax increased the BMD at the lumbar spine and the hipbone in males (p = 0.028 and 0.03, respectively) but only at the lumbar spine in females (p = 0.022).
After a long periods after renal transplantation, the detrimental effects of steroid and immunosuppressive agents on bone condition diminished. Short-term Fosamax administration effectively improves BMD in these patients. The efficacy of Fosamax differed between male and female renal transplant patients.
PMCID: PMC3502459  PMID: 23185261
15.  A Case of Teriparatide on Pregnancy-Induced Osteoporosis 
Journal of Bone Metabolism  2013;20(2):111-114.
Pregnancy-induced osteoporosis is a rare disorder characterized by fragility fracture and low bone mineral density (BMD) during or shortly after pregnancy, and its etiology is still unclear. We experienced a case of a 39-year-old woman who suffered from lumbago 3 months after delivery. Biochemical evidence of increased bone resorption is observed without secondary causes of osteoporosis. Radiologic examination showed multiple compression fractures on her lumbar vertebrae. We report a case of patient with pregnancy-induced osteoporosis improved her clinical symptom, BMD and bone turnover marker after teriparatide therapy.
PMCID: PMC3910313  PMID: 24524067
Osteoporosis; Pregnancy; Teriparatide
16.  Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study 
Journal of Thyroid Research  2014;2014:165487.
Background. Graves' disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves' disease (hyperthyroidism, goiter, and presence of orbitopathy) at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves' hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves' hyperthyroidism, entitled “Remission Induction and Sustenance in Graves' Disease (RISG).” Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves' disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25–30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves' disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.
PMCID: PMC3945164
17.  Effects of Long-Term Combination Treatment with Valproate and Atypical Antipsychotics on Bone Mineral Density and Bone Metabolism in Premenopausal Patients with Bipolar Disorder: A Preliminary Study 
Psychiatry Investigation  2011;8(3):256-261.
We investigated bone mineral density (BMD) and bone metabolism in female bipolar patients who were undergoing long-term treatment with valproate combined with a low-dose atypical antipsychotic.
Nineteen premenopausal women with bipolar disorder who were treated with valproate combined with atypical antipsycho-tics for at least 2 years were evaluated. The BMD was measured at lumbar spine and femur sites using dual-energy X-ray absorptiometry (DE-XA). The biochemical markers of bone turnover and circulating levels of gonadal hormones were assessed. Subjects with abnormal DEXA scans were compared to those with normal scans.
Nine (47%) of nineteen subjects showed osteopenia or osteoporosis. The T-score for subjects with abnormal DEXA scans was -1.988. Decreased BMD was more prominent in the proximal femur than in the lumbar spine. Subjects with abnormal DEXA scans had high phosphorus and low testosterone levels relative to subjects with normal scans (p=0.008 and p=0.028, respectively). There was a significant negative correlation between phosphorus, osteocalcin, and femur neck BMD (p<0.05). However, multivariate analysis did not show a significant association between femur and lumbar BMD and biochemical markers of bone turnover.
Long-term treatment with valproate combined with low-dose atypical antipsychotics may adversely affect BMD in premenopausal women with bipolar disorder. A prospective, controlled-study with a larger population is warranted, and assessment of BMD and bone metabolism should be taken into consideration in long-term therapy with valproate and atypical antipsychotics.
PMCID: PMC3182392  PMID: 21994514
Bipolar disorder; Bone density; Bone metabolism; Females; Valproate
18.  Genetic and environmental factors affecting bone mineral density in large families. 
Postgraduate Medical Journal  1998;74(872):349-354.
This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.
PMCID: PMC2360948  PMID: 9799889
19.  Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We? 
Journal of Osteoporosis  2011;2011:704015.
In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men.
PMCID: PMC3246740  PMID: 22220284
20.  Bone metabolism and mineral density following renal transplantation 
Archives of Disease in Childhood  2000;83(2):146-151.
AIM—To study bone turnover following renal transplantation using a panel of biochemical markers and to correlate the results with both areal and volumetric bone mineral density (BMD).
PATIENTS—A total of 31 patients aged 18.1 years were transplanted 5.4 years before this study. Control patients (n = 31) were age and gender matched.
METHODS—In addition to measurement of biochemical markers, BMD was measured by single photon absorptiometry and peripheral quantitative computed tomography on the non-dominant radius.
RESULTS—Patients had reduced glomerular filtration rate, raised concentrations of serum phosphate, serum procollagene type I carboxy terminal propeptide, osteocalcin, and serum procollagene type I cross linked carboxy terminal telopeptide. The differences were still significant if only patients with normal intact parathyroid hormone were considered. BMD single photon absorptiometry Z score for age was significantly decreased. Following standardisation for height the differences were no longer present. With volumetric techniques patients had normal trabecular but decreased cortical and total BMD compared to age matched controls, but there was no difference from height matched controls.
CONCLUSION—Markers of bone turnover are increased following renal transplantation. However, the biochemical analysis did not allow conclusions to be drawn on the bone mineral content. BMD single photon absorptiometry Z score corrected for height and BMD measured by quantitative computed tomography compared to height matched controls were normal in paediatric renal transplantation patients. Height matched controls should be used in both areal and volumetric BMD measurements in states of growth failure.

PMCID: PMC1718413  PMID: 10906024
21.  Three-year experience with combined treatment with alendronate and alfacalcidol in Japanese patients with severe bone loss and osteoporotic fracture 
Combined treatment with alendronate and alfacalcidol is more useful to increase bone mineral density (BMD) than alendronate or alfacalcidol alone. A retrospective study was conducted to investigate the 3-year outcome of combined treatment with alendronate and alfacalcidol in patients with severe bone loss (BMD ≤ 50% of the young adult mean) and osteoporotic fracture.
Thirty-four patients (six men and 28 postmenopausal women) with primary or secondary osteoporosis who had been treated with alendronate and alfacalcidol for more than 3 years were analyzed. The lumbar spine or total hip BMD and bone turnover markers were monitored, and the incidence of osteoporotic fractures was assessed.
The urinary level of cross-linked N-terminal telopeptides of type I collagen and serum level of alkaline phosphatase significantly decreased (−42.5% at 3 months and −18.9% at 3 years), and the lumbar spine BMD, but not the total hip BMD, significantly increased (14.8% at 3 years), compared with the baseline values. However, the incidence of vertebral and nonvertebral fractures was 26.5% and 2.9%, respectively, suggesting a high incidence of vertebral fractures.
The results of the present study suggest that combined treatment with alendronate and alfacalcidol may be useful to reduce bone turnover and increase the lumbar spine BMD in patients with severe bone loss and osteoporotic fracture. However, its efficacy against vertebral fractures appears not to be sufficient. Thus, anabolic agents such as teriparatide should be taken into consideration as first-line drugs in patients with severe osteoporosis.
PMCID: PMC3132096  PMID: 21753888
osteoporosis; fragility fracture; bone mineral density; bone turnover
22.  The Association of Serum Osteocalcin with the Bone Mineral Density in Post Menopausal Women 
Background: The markers of bone remodelling, such as serum osteocalcin, may be used to assess osteoporosis and to predict the fracture risk in elderly persons, especially in women. The bone mineral density which reflects the bone mass and strength, also predicts osteoporotic related hip fractures. So, this work highlights the association between the bone turnover and the bone mass and strength.
Aim: To assess the association between the biochemical markers of bone remodeling and osteocalcin with the bone mineral density in non osteoporotic and osteoporotic women among post menopausal subjects.
Materials and Methods: Sixty postmenopausal women whose ages ranged from 55-65 years included in this study, were further divided into group 1 (thirty non osteoporotic subjects) and group 2 (thirty osteoporotic subjects). For all the subjects, serum osteocalcin was measured by ELISA. BMD was measured by the Dual Energy X- Ray Absorptiometry (DXA) scan. The women with osteoporosis were diagnosed, based on the T- score of the bone mineral density, by the DXA scan. The Student’s “t” test was performed between the variables of both the groups and a correlation test was also performed between osteocalcin and BMD by using SPSS.
Results: A negative correlation was found between the osteocalcin level and the bone mineral density in post menopausal women. The mean values of both serum osteocalcin and BMD between the osteoporotic and the non osteoporotic subjects were statistically significant.
Conclusion: An increased bone turnover coincides with the trabecular deterioration in osteoporotic women of the post menopausal age group. A combination of biochemical markers and BMD may be a better predictor of the fracture risk than when it was assessed by either alone. The biochemical markers of the bone turnover cannot be a substitute for the serial BMD measurement, but they may be useful when they are considered in conjunction with the BMD measurement.
PMCID: PMC3681044  PMID: 23814717
BMD; Osteocalcin; Osteoporosis
23.  Lack of association between estrogen receptor β dinucleotide repeat polymorphism and autoimmune thyroid diseases in Japanese patients 
The autoimmune thyroid diseases (AITDs), such as Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of complex interactions between predisposing genes and environmental triggers. Susceptibility to AITDs is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. Recently, estrogen receptor (ER) β, located at human chromosome 14q23-24.1, was identifed. We analyzed a dinucleotide (CA)n repeat polymorphism located in the flanking region of ERβ gene in patients with AITDs and in normal subjects. High heterozygosity makes this polymorphism a useful marker in the genetic study of disorders affecting female endocrine systems. We also correlated a ERβ gene microsatellite polymorphism with bone mineral density (BMD) in the distal radius and biochemical markers of bone turnover in patients with GD in remission.
Fourteen different alleles were found in 133 patients with GD, 114 patients with HT, and 179 controls subjects. The various alleles were designated as allele*1 through allele*14 according to the number of the repeats, from 18 to 30. There was no significant difference in the distributions of ERβ alleles between patient groups and controls. Although recent study demonstrated a significant relation between a allele*9 in the ERβ gene and BMD in postmenopausal Japanese women, there were no statistically significant interaction between this allele and BMD in the distal radius, nor biochemical markers in patients with GD in remission.
The present results do not support an association between the ERβ microsatellite marker and AITD in the Japanese population. We also suggest that the ERβ microsatellite polymorphism has at most a minor pathogenic importance in predicting the risk of osteoporosis as a complication of GD.
PMCID: PMC29094  PMID: 11180758
24.  Effects of Low-Dose Testosterone Undecanoate Treatment on Bone Mineral Density and Bone Turnover Markers in Elderly Male Osteoporosis with Low Serum Testosterone 
This prospective 2-year, single-center, randomized, placebo-controlled, open-label clinical trial was performed to evaluate the efficacy of low-dose testosterone undecanoate (TU) treatment on bone mineral density (BMD) and biochemical markers of bone turnover in elderly male osteoporosis with low serum testosterone. A total of 186 elderly male osteoporosis patients with low serum testosterone were randomized into three groups: low-dose TU (20 mg, per day), standard-dose TU (40 mg, per day), and placebo group with a 24-month followup. Since the 6th month in standard-dose TU group or since the 12th month followup in low-dose TU group and throughout the study, lumbar spine and femoral neck BMD and serum levels of free testosterone, estradiol, and bone alkaline phosphatase significantly increased. There were no significant differences between groups of low-dose TU and standard dose TU in the percentage of changes of these data since the 18th month followup and throughout the study. No side effects on prostate glands including prostate specific antigen were found. In conclusion, low-dose TU (20 mg, per day) may be a cost effective and safe protocol for treating elderly male osteoporosis with low serum testosterone.
PMCID: PMC3603196  PMID: 23533404
25.  Noninvasive assessment of bone health in Indian patients with chronic kidney disease 
Indian Journal of Nephrology  2013;23(3):161-167.
Abnormalities in mineral and bone disease are common in chronic kidney disease (CKD). Evaluation of bone health requires measurement of parameters of bone turnover, mineralization, and volume. There are no data on bone health in CKD patients from India. In this cross-sectional study, we evaluated serum biomarkers of bone turnover: Bone-specific alkaline phosphatase (BAP) and total deoxypyridinoline (tDPD) along with parathyroid hormone, 25(OH) vitamin D, and bone mineral density (BMD) using dual absorption X-ray absorptiometry in a cohort of 74 treatment-naive patients with newly diagnosed stage 4 and 5 CKD (age 42 ± 14.5 years, 54 men) and 52 non-CKD volunteers (age 40.2 ± 9.3 years, 40 men). Compared to the controls, CKD subjects showed elevated intact PTH (iPTH), BAP, and tDPD and lower BMD. There was a strong correlation between iPTH and BAP (r = 0.88, P < 0.0001), iPTH and tDPD (r = 0.51, P < 0.0001), and BAP and tDPD (r = 0.46, P = 0.0004). The iPTH elevation was greater than twice the upper range of normal in 73% cases, and BAP was >40 U/L in 66% cases. The combination of these markers suggests high turnover bone disease in over 60% cases. The prevalence of osteopenia and osteoporosis was 37% and 12%, respectively. Osteoporotic subjects had higher iPTH, BAP, and tDPD, suggesting a role of high turnover in genesis of osteoporosis. Vitamin D deficiency was seen in 80%, and another 13% had insufficient levels. Vitamin D correlated inversely with BAP (r = −0.3, P = 0.009), and levels were lower in those with iPTH >300 pg/ml (P = 0.0.04). In conclusion, over 60% of newly diagnosed Indian stage 4–5 CKD patients show biochemical parameters consistent with high turnover bone disease. High turnover could contribute to the development of osteoporosis in CKD subjects. Deficiency of 25 (OH) vitamin D is widespread and seems to have a role in the genesis of renal bone disease. Studies on the effect of supplementation of native vitamin D are needed.
PMCID: PMC3692139  PMID: 23814412
Bone mineral density; bone-specific alkaline phosphatase; chronic kidney disease; deoxypyrinolidine; parathyroid hormone; renal osteodystrophy; vitamin D

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